The present invention is directed to a new use for Erythropoetin (xe2x80x9cEPOxe2x80x9d), such as EPO alpha, for treating hepatitis C and/or anemia caused by hepatitis C treatment. Accordingly, the invention involves using EPO with hepatitis C treatment, such as Ribavirin (xe2x80x9cRBVxe2x80x9d) and/or interferon such as alpha-interferon (xe2x80x9cxcex1-IFNxe2x80x9d or xe2x80x9cIFNxe2x80x9d); and thus, the invention pertains to methods involving administration of EPO, RBV and xcex1-IFN, or EPO and RBV, and compositions
Various documents are cited herein, e.g., in the text and/or in a reference section. There is no admission that any of the various documents cited in this text are prior art as to the present invention. Any document having as an author or inventor person or persons named as an inventor herein is a document that is not by another as to the inventive entity herein. All documents cited in this text (xe2x80x9cherein cited documentsxe2x80x9d) and all documents cited or referenced in herein cited documents are hereby incorporated herein by reference. All specifications, manufacturer""s data sheets, and the like for products referenced herein, and all documents cited therein, are hereby incorporated herein by reference.
Erythropoietin (xe2x80x9cEPOxe2x80x9d) is one of the red blood cell stimulating factors in the human body. Recombinant technology has made manufacture of this stimulating factor colony possible and its use in treating anemia caused by cancer chemotherapy, acquired immune deficiency syndrome (xe2x80x9cAIDSxe2x80x9d) and renal failure. The recombinant product has been shown to be biologically identical to human erythropoietin.
A normal response to anemia in humans is the release of EPO and a corresponding rise in the hemoglobin level. There can be either an inadequate production of EPO or a lack of response to EPO by the bone marrow. When ribavirin is administered by itself, it gets pumped into red blood cells and, once inside, gets phosphorylated. After it is phosphorylated, the ribavirin cannot get out of the red blood cell and its concentration builds up until the red blood cell bursts (hemolysis). This anemia can be severe and even life threatening, particularly in people with heart disease. The normal response to a hemolytic anemia is the release of EPO which stimulates the bone marrow to produce more red blood cells, and immature red blood cells (reticulocytes) will be discovered in the peripheral blood smear. When interferon is administered with ribavirin, however, it blocks the normal response of the bone marrow to respond to the anemia and the reticulocyte response is blunted. Administration of exogenous EPO such as Epoetin alpha can overcome this response and cause the bone marrow to produce more red blood cells, overcoming the inhibitory effect of the interferon.
Recently, great importance has been placed on using ribavirin to eradicate hepatitis C. Hepatitis C, according to the Centers for Disease Control (xe2x80x9cCDCxe2x80x9d), afflicts over 3.9 million people in the United States today. Cirrhosis and liver failure caused by hepatitis C are the leading causes of liver transplant in the U.S. today. It is also an important global problem with as many as 50 million people afflicted with hepatitis C worldwide. The combination of interferon and ribavirin has been an approved treatment for hepatitis C since 1998. The addition of ribavirin has more than doubled the effect of the treatment to the hepatitis C virus. Clinical data from recent licensing trials shows that patients who receive at least 10.6 mg/kg of ribavirin have a sustained virologic response rate of over 40%, whereas those receiving less than that amount have a SVR (response) rate of only 28%. The maximum benefit is gained from a dose of ribavirin that is about 13 mg/kg. Such high doses of ribavirin cause a substantial increase of almost 50% in the incidence of anemia. The normal management of this would be to reduce the ribavirin dose and thereby reduce the efficacy of the interferon/ribavirin combination therapy. However, this would defeat the purpose of the hepatitis C treatment.
With respect to treating anemia caused by hepatitis C treatment in conjunction with ribavirin, reference is made to the following:
Albrecht, U.S. Pat. No. 6,172,046 B1, relates to a method of treating a patient having chronic hepatitis C infection. To eradicate detectable hepatitis C virus RNA, a combination therapy using a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of from 20 up to 80 weeks is disclosed.
Draper, U.S. Pat. No. 5,610,054, relates to an enzymatic RNA molecule which cleaves RNA of the hepatitis C virus. Draper, U.S. Pat. No. 5,869,253, relates to an enzymatic RNA molecule which cleaves RNA encoding hepatitis C virus (xe2x80x9cHCVxe2x80x9d) RNA, wherein the enzymatic RNA molecule comprises a substrate binding site and a nucleotide sequence within or surrounding the substrate binding site wherein the nucleotide sequence imparts to the enzymatic RNA molecule activity for the cleavage of the HCV RNA. Draper, U.S. Pat. No. 6,132,966, relates to an enzymatic nucleic acid molecule which inhibits hepatitis C virus replication.
Ise et al., U.S. Pat. No. 5,399,551, relates to an enhancer for antianemia effect of erythropoietin using a spherical carbon as an active ingredient in an amount effective for treating anemia in combination with erythropoietin. The enhancer is orally administered. The antianemia effect of erythropoietin can be enhanced, the dosage of erythropoietin can be decreased, and side effects from erythropoietin can be reduced. The invention further discloses a method of augmenting the anti-anemia effect of Erythropoetin by administering to a patient an effective amount of a spherical carbon in combination with a portion of an effective amount of Erythropoetin for treating anemia.
Population Pharmacokinetic and Pharmacodynamic Analysis of Ribavirin in Patients with Chronic Hepatitis C, by J. Frank Jen, Paul Glue, Samir Gupta, Demetrius Zambas and Gerald Hajian (Therapeutic Drug Monitoring, Vol. 22, No. 3, 2000) (xe2x80x9cPopulationxe2x80x9d), reported that
xe2x80x9cAthough anemia is a well-established adverse effect of ribavirin therapy, the association between drug concentrations and extent of anemia has not been thoroughly investigated. Earlier reports (22, 23) found that greater mean falls in hemoglobin were associated with higher daily ribavirin doses.
Despite the mean trends the variability of these data was high, suggesting that it would not be possible to establish a concentration range below which hemolysis would not occur, or above which anemia was inevitable. From a practical perspective, the most appropriate method of dealing with treatment related anemia would appear to be through dose reduction of ribavirin, although this analysis indicates that this should be based on individual hemotologic responses to ribavirin rather than based on serum ribavirin concentrations.xe2x80x9d
Thus, there is teaching in the art to reduce RBVxe2x80x94reduce the HCV treatmentxe2x80x94to address anemia. Teachings such as this teach away from addressing anemia by other means and therefore teach away from the present invention.
Poduslo et al., U.S. Pat. No. 5,604,198, relates to a method of enhancing an ability of a neurologically active compound to penetrate the blood nerve barrier (xe2x80x9cBNBxe2x80x9d) or blood brain barrier (xe2x80x9cBBBxe2x80x9d), by administering a conjugate comprising the neurologically active compound linked to a carrier molecule that has been shown to have a substantial permeability coefficient across the BNB and BBB. Poduslo et al., U.S. Pat. No. 5,670,477, relates to a method of enhancing the ability of a neurologically active compound to penetrate the blood nerve barrier (xe2x80x9cBNBxe2x80x9d) or blood brain barrier (xe2x80x9cBBBxe2x80x9d) comprising parenterally administering to a mammal in need of treatment with the neurologically active compound, a conjugate consisting of an effective amount of the neurologically active compound linked to a polyamine having a substantial permeability coefficient across the BNB or BBB.
Strickland, U.S. Pat. No. 5,661,125, relates to stable compositions of erythropoietin that contain an antimicrobial preservative thereby providing a multi-dose formulation. Preservatives useful in the pharmaceutical compositions of the invention include benzyl alcohol, parabens, phenol and mixtures thereof. Other additives, including buffers, may be included in the composition.
Tam, U.S. Pat. No. 6,063,772, relates to administering ribavirin to a patient in a dosage range which is effective to modulate lymphokine expression in activated T cells. In particular, ribavirin is used to suppress Th2-mediated T cell responses and promote Th1-mediated T cell response. Instead of administering ribavirin in its well-recognized role as an anti-viral agent, ribavirin is thus used in the treatment of imbalances in lymphokine expression. Such imbalances may be found to be concomitants of allergic atopic disorders, such as allergic asthma and atopic dermatitis, helminthes infection and leishmaniasis, and various primary and secondary immunodeficiencies, which may or may not also be associated with viral infection.
Interferon (IFN) and Ribavirin (RBV) Therapy for Hepatitis C (HCV) in HIV-Coinfected Patients, 12 Month Follow-Up, 7th Conference on Retroviruses and Opportunistic Infections, at the Birth of a Century, Research Toward Ending AIDS, Program and Abstracts, Jan. 30-Feb. 2, 2000, by K. Weisz, D. Goldman, A. Talal, M. Malicdem and D. Dieterich, reported that (1) IFN alone does not adversely affect HIV RNA, and can have little effect on HCV RNA; (2) IFN and RBV have little effect on HIV RNA clinically, and have a sizeable effect on HCV RNA; (3) anemia, a side effect of RBV, can be successfully treated with erythropoietin. However, this study fails to teach or suggest the present invention as it did not involve co-administered or concomitant administration as herein; and, because the study concerned and HIV positive patients, not HCV patients who are HIV negative or immunocompetent, as there is a prejudice in the art against employing EPO in immunocompetent individuals because EPO administration can give rise to anti-EPO antibodies. (However, methods, kits and compositions of the invention are not necessarily excluded from being employed with respect to immunocompromised individuals.)
Yatvin et al., U.S. Pat. No. 5,543,390, relates to a method and a reagent for delivering biologically active compounds to phagocytic mammalian cells. The patent also relates to an uptake of such biologically active compounds by phagocytic cells and delivery of such compounds to specific sites intracellularly. The invention more particularly relates to methods of facilitating the entry of antimicrobial drugs and other agents into phagocytic cells and for targeting such compounds to specific organelles within the cell. The ""390 patent further relates to compositions of matter and pharmaceutical embodiments of such compositions comprising conjugates of such antimicrobial drugs and agents covalently linked to particulate carriers generally termed microparticles. In particular embodiments, the antimicrobial drug is covalently linked to a microparticle via an organic linker molecule which is the target of a microorganism-specific protein having enzymatic activity. The 390 patent also provides cell targeting of drugs wherein the targeted drug is only released in cells infected with a particular microorganism. Alternative embodiments of such specific drug delivery compositions also contain polar lipid carrier molecules effective in achieving intracellular organelle targeting in infected phagocytic mammalian cells. Particular embodiments of such conjugates comprise antimicrobial drugs covalently linked both to a microparticle via an organic linker molecule and to a polar lipid compound, to facilitate targeting of such drugs to particular subcellular organelles within the cell. Also provided are porous microparticles impregnated with antimicrobial drugs and agents wherein the surface or outside extent of the microparticle is covered with a degradable coating that is specifically degraded within an infected phagocytic mammalian cell. Methods of inhibiting, attenuating, arresting, combating and overcoming microbial infection of phagocytic mammalian cells in vivo and in vitro are also provided. While technology in the 390 patent may be useful in the practice of the herein invention, the 390 patent fails to teach or suggest the present invention.
Yatvin et al., U.S. Pat. No. 5,543,391, relates to a composition having a biologically-active compound that is an antimicrobial drug, a porous microparticle, and an organic coating material, wherein the biologically-active compound is impregnated within the porous microparticle, and the microparticle is coated with the organic coating moiety, and wherein the organic coating material comprises a compound that is specifically degraded inside a phagocytic mammalian cell infected with a microorganism to allow release of the biologically-active compound within the infected cell.
Foregoing patents and/or other background information discussed may involve either an EPO composition or an EPO enhancer. However, none of the patents foregoing patents and/or background information discloses or suggests using EPO as an anti-anemia treatment in conjunction with the ribavirin-interferon-alpha treatment for HIV negative or immunocompetent hepatitis C patients and/or in a co-administration regimen and/or via a kit, as herein.
And, in this regard, it is again mentioned that administration of EPO can give rise to anti-EPO antibodies, inter alia, such that there may be a prejudice against administration of EPO to immuno-competent (e.g., HIV negative) individuals.
Thus, it is believed that heretofore the present invention has not been taught or suggested.
It is an object of the present invention to provide a new use of Erythropoetin (xe2x80x9cEPOxe2x80x9d) to treat an anti-anemia condition caused by the combination treatment of ribavirin and interferon-alpha. It is another object of the present invention to provide a method of administering EPO to patients with ribavirin-induced anemia to counteract a hemolytic effect and to allow patients to take the maximum effective dosage of ribavirin and interferon-alpha necessary to eradicate hepatitis C.
It is and has been surprisingly found that EPO works the same in both HIV positive and HIV negative patients with HCV.
In this text, the term xe2x80x9ccomprisingxe2x80x9d, xe2x80x9ccomprisexe2x80x9d, xe2x80x9ccomprisesxe2x80x9d and other forms of xe2x80x9ccomprisexe2x80x9d can have the meaning described to these terms in U.S. Patent Law and can mean xe2x80x9cincludingxe2x80x9d, xe2x80x9cincludexe2x80x9d, xe2x80x9cincludesxe2x80x9d and other forms of xe2x80x9cincludexe2x80x9d.
Co-administering is administration at the same time or at about the same time, i.e., via a composition or kit containing all of EPO, interferon-alpha and ribavirin; for instance, co-administering can involve a sequential administration of RBV, EPO and IFN e.g., via a visit to a healthcare provider, or via patient self administration.
More in particular, RBV typically is provided and administered in solid, e.g., capsule or tablet form or in the form of an inhaler, with the tablet or capsule being usually employed with respect to HCV. Patients usually take 2 to 3 tablets or capsules of RBV/day (e.g., Rebetol, such as 800 or 1000-1200 mg/daily). IFN is provided in an injectable form, as is EPO. For instance, Intron A (IFN) injection in a 3 MIU dose can be administered three times weekly; and PEG-IntronNT (pegylated IFN) injection in a 0.5 or 1.5 mcg/kg dose can be administered once weekly (QW). Combinations of RBV and IFN can include: PEG-IntronNT injection 1.5 mcg/kg once weekly (QW) plus Rebetol capsules 800 mg/daily for 48 weeks (PEG 1.5/R); PEG-Intron 1.5 mcg/kg QW plus Rebetol 1000-1200 mg/daily for four weeks followed by PEG-Intron 0.5 mcg/kg QW plus Rebetol 1000-1200 mg/daily for 44 weeks (Peg 0.5/R); or Intron A injection 3 MIU/three times weekly plus Rebetol Capsules 1000-1200 mg/daily for 48 weeks (Rebetron). Patients can self-administer EPO, RBV and IFN.
The invention envisages kits that contain EPO, RBV and IFN, such that the patient can administer the EPO, RBV and IFN; e.g., RBV orally twice daily (e.g. once in morning, once in evening or three times daily including a morning dose), IFN once weekly or three times weekly via injection, and EPO at least once weekly via injection. The patient can therefore obtain a one-week, two-week, three-week, monthly, bimonthly, three-month, four-month, five-month, six-month, seven-month, eight-month, nine-month, ten-month, eleven-month, or annual supply of EPO, RBV and IFN, via a kit of the invention.
The kit thus advantageously contains EPO e.g., for injection, IFN e.g., for injection, suitable devices for administration via injection (e.g., syringes) if components are supplied for administration via injection, RBV e.g., tablets or capsules, and optionally (but advantageously) instructions for administration/use. The patient can therefore each day self-administer or be administered the RBV (e.g., orally), advantageously with a first dose in the morning or upon awakening. On selected day or day(s), such as in the morning or upon awakening, with the first dose of RBV, the patient can then also administer IFN. And, on selected day or day(s), such as in the morning or upon awakening, also with a first dose of RBV, the patient can additionally administer the EPO.
Thus, the patient can be having a co-administration of EPO and RBV.
Moreover, at least once weekly, the patient can be having co-administration of RBV, IFN and EPO, advantageously at the same time, e.g., via oral administration of RBV and sequential injections of IFN and EPO.
The patient self administrations can, of course, be performed by a healthcare provider.
Even more advantageous, the EPO and IFN can be provided for admixture and/or in an admixed state, so that the EPO and IFN administration is via one injection of a combination of EPO and IFN. Thus, when the EPO and IFN are to be co-administered, it may be possible to admix them for a single injection containing both. However, an injection for each of the EPO and IFN and oral administration of RBV are presently preferred.
A preferred embodiment involves a kit containing EPO for once weekly administration by injection, IFN for once weekly administration by injection, and RBV for twice daily oral administration. The kit can contain instructions for administration. The kit can also contain devices for administration via injection. Again, the kit can contain an xe2x80x9cNxe2x80x9d week, wherein xe2x80x9cNxe2x80x9d is an integer advantageously from 1-52 (e.g., one week, or two week, or three week, or four week, or five week, or six week, or seven week, or eight week, or nine week, or ten week, or eleven week, or 12 week or 13 week or 14 week etc. up to 52 week) supply of EPO, IFN and RBV.
Accordingly, the invention provides methods for administering RBV and EPO or RBV, EPO and IFN for treatment of HCV and/or anemia caused by HCV, as well as compositions containing EPO and IFN, and kits containing RBV and EPO, or, RBV, EPO and IFN, with such kits optionally containing instructions for administration and/or devices for administration, and the EPO and IFN, if together in the kit, can be in forms so that when co-administered they can be admixed prior thereto and/or they are in an admixed form for co-administration.
In instances where the HCV can be treated by RBV without IFN, embodiments can involve the foregoing, with the IFN omitted.
The invention further comprehends methods for co-administering RBV and EPO or RBV, EPO and IFN, as well as compositions containing EPO and IFN, or RBV and EPO, or RBV, IFN and EPO.
These and other objects and embodiments of the invention are provided in, or are obvious from, the following detailed description of the invention.